Global Microbiota-Dependent Histone Acetylation Patterns Are Irreversible and Independent of Short Chain Fatty Acids.

BACKGROUND AND AIMS: Although germ-free mice are an indispensable tool in studying the gut microbiome and its effects on host physiology, they are phenotypically different than their conventional counterparts. While antibiotic-mediated microbiota depletion in conventional mice leads to physiologic alterations that often mimic the germ-free state, the degree to which the effects of microbial colonization on the host are reversible is unclear. The gut microbiota produce abundant short chain fatty acids (SCFAs), and previous studies have demonstrated a link between microbial-derived SCFAs and global hepatic histone acetylation in germ-free mice. APPROACH AND RESULTS: We demonstrate that global hepatic histone acetylation states measured by mass spectrometry remained largely unchanged despite loss of luminal and portal vein SCFAs after antibiotic-mediated microbiota depletion. In contrast to stable hepatic histone acetylation states, we see robust hepatic transcriptomic alterations after microbiota depletion. Additionally, neither dietary supplementation with supraphysiologic levels of SCFA nor the induction of hepatocyte proliferation in the absence of microbiota-derived SCFAs led to alterations in global hepatic histone acetylation. CONCLUSIONS: These results suggest that microbiota-dependent landscaping of the hepatic epigenome through global histone acetylation is static in nature, while the hepatic transcriptome is responsive to alterations in the gut microbiota.

Clinical presentation and surgical outcomes in primary aldosteronism differ by race.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension; early diagnosis and intervention correlate with outcomes. We hypothesized that race may influence clinical presentation and outcomes. METHODS: We conducted a retrospective analysis of patients with PA (1997-2017) who underwent adrenal vein sampling (AVS). Patients were classified by self-reported race as black or non-black. Improvement was defined as postoperative decrease in mean arterial pressure (MAP), antihypertensive medications (AHM), or both. RESULTS: Among patients undergoing AVS (n = 443), 287 underwent adrenalectomy. Black patients (28.2%) had higher body mass index (33.9 vs 31.8 kg/m2 ; P = .01), longer median duration of hypertension (12 vs 10 years; P = .003), higher modified Elixhauser comorbidity index (2 vs 1; P = .004), and lower median income ($47 134 vs $78 280; P < .001). Black patients had similar aldosterone:renin ratios (150 vs 135.6 [ng/dL]/[ng·mL·-1 hr-1 ]; P = .23) compared to non-blacks. At long-term follow-up, black patients had a similar requirement for AHM (1 vs 0; P = .13) but higher MAP (100.6 vs 95.3 mm Hg; P = .004). CONCLUSION: Black patients present with longer duration of hypertension and more comorbidities. They are equally likely to lateralize on AVS, suggesting similar disease phenotype. However, black patients demonstrate less improvement with adrenalectomy; this may reflect a delay in diagnosis or concomitant essential hypertension.

The Microbiome-Host Interaction as a Potential Driver of Anastomotic Leak.

PURPOSE OF REVIEW: The goal of this paper is to review current literature on the gut microbiome within the context of host response to surgery and subsequent risk of developing complications, particularly anastomotic leak. We provide background on the relationship between host and gut microbiota with description of the role of the intestinal mucus layer as an important regulator of host health. RECENT FINDINGS: Despite improvements in surgical technique and adherence to the tenets of creating a tension-free anastomosis with adequate blood flow, the surgical community has been unable to decrease rates of anastomotic leak using the current paradigm. Rather than adhere to empirical strategies of decontamination, it is imperative to focus on the interaction between the human host and the gut microbiota that live within us. The gut microbiome has been found to play a potential role in development of post-operative complications, including but not limited to anastomotic leak. Evidence suggests that peri-operative interventions may have a role in instigating or mitigating the impact of the gut microbiota via disruption of the protective mucus layer, use of multiple medications, and activation of virulence factors. The microbiome plays a potential role in the development of surgical complications and can be modulated by peri-operative interventions. As such, further research into this relationship is urgently needed.

Risk factors affecting operative approach, conversion, and morbidity for adrenalectomy: a single-institution series of 402 patients.

BACKGROUND: Risk factors for selecting patients for open adrenalectomy (OA) and for conversion are limited in most series. This study aimed to investigate variables that are important in selecting patients for OA, predict risk of conversion from laparoscopic adrenalectomy (LA), and impact 30-day outcomes of OA and LA. METHODS: A retrospective cohort study of prospectively collected data was conducted. Patients (≥ 16 years old) who underwent adrenalectomy in the Division of General Surgery at Barnes-Jewish Hospital (1993-2010) were grouped by operative approach (LA vs. OA) and compared using nonparametric tests and regression analyses (α < 0.05). RESULTS: In total, 402 patients underwent 422 adrenalectomies. Compared to LA patients, those in the OA group were older (p = 0.02), had higher ASA scores (p = 0.04), larger tumor size (p < 0.01), and fewer functioning lesions (p < 0.01). OA patients more often required concurrent procedures (p < 0.01), had a longer operative time (p = 0.04), more intraoperative complications (p = 0.02), higher estimated blood loss (EBL), and larger transfusion requirement. Preoperative factors that predicted selection for OA were higher patient age (p = 0.01), higher ASA score (p = 0.03), larger tumor size (p < 0.01), nonfunctioning lesion (p < 0.01), diagnosis of adrenocortical carcinoma (p < 0.01), and the need for concomitant procedures (p < 0.01). Conversion to open or hand-assisted approach occurred in 6.2 % of LA patients. Preoperative risks for conversion included large tumor size (>8 cm) and need for concomitant procedures (p < 0.01). Multivariate analysis revealed that large indeterminate adrenal mass, adrenocortical carcinoma, tumor size (>6 cm), an open operation, conversion, concomitant procedures, operative time >180 min, and EBL >200 mL were predictors of 30-day morbidity. CONCLUSIONS: Adrenal tumor size and need for concurrent procedures significantly impact the selection of patients for OA, the likelihood of conversion, and perioperative morbidity. These metrics should be considered when assessing operative approach and risks for adrenalectomy.

Relationships between body fat distribution and metabolic syndrome traits and outcomes: A mendelian randomization study.

BACKGROUND: Obesity is a complex, multifactorial disease associated with substantial morbidity and mortality worldwide. Although it is frequently assessed using BMI, many epidemiological studies have shown links between body fat distribution and obesity-related outcomes. This study examined the relationships between body fat distribution and metabolic syndrome traits using Mendelian Randomization (MR). METHODS/FINDINGS: Genetic variants associated with visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT), as well as their relative ratios, were identified from a genome wide association study (GWAS) performed with the United Kingdom BioBank. GWAS summary statistics for traits and outcomes related to metabolic syndrome were obtained from the IEU Open GWAS Project. Two-sample MR and BMI-controlled multivariable MR (MVMR) were performed to examine relationships between each body fat measure and ratio with the outcomes. Increases in absolute GFAT were associated with a protective cardiometabolic profile, including lower low density lipoprotein cholesterol (ß: -0.19, [95% CI: -0.28, -0.10], p < 0.001), higher high density lipoprotein cholesterol (ß: 0.23, [95% CI: 0.03, 0.43], p = 0.025), lower triglycerides (ß: -0.28, [95% CI: -0.45, -0.10], p = 0.0021), and decreased systolic (ß: -1.65, [95% CI: -2.69, -0.61], p = 0.0019) and diastolic blood pressures (ß: -0.95, [95% CI: -1.65, -0.25], p = 0.0075). These relationships were largely maintained in BMI-controlled MVMR analyses. Decreases in relative GFAT were linked with a worse cardiometabolic profile, with higher levels of detrimental lipids and increases in systolic and diastolic blood pressures. CONCLUSION: A MR analysis of ASAT, GFAT, and VAT depots and their relative ratios with metabolic syndrome related traits and outcomes revealed that increased absolute and relative GFAT were associated with a favorable cardiometabolic profile independently of BMI. These associations highlight the importance of body fat distribution in obesity and more precise means to categorize obesity beyond BMI.

Dietary fiber-based regulation of bile salt hydrolase activity in the gut microbiota and its relevance to human disease.

Complications of short bowel syndrome (SBS) include malabsorption and bacterial overgrowth, requiring prolonged dependence on parenteral nutrition (PN). We hypothesized that the intolerance of whole food in some SBS patients might be due to the effect of dietary fiber on the gut microbiome. Shotgun metagenomic sequencing and targeted metabolomics were performed using biospecimens collected from 55 children with SBS and a murine dietary fiber model. Bioinformatic analyses were performed on these datasets as well as from a healthy human dietary intervention study. Compared to healthy controls, the gut microbiota in SBS had lower diversity and increased Proteobacteria, a pattern most pronounced in children on PN and inversely correlated with whole food consumption. Whole food intake correlated with increased glycoside hydrolases (GH) and bile salt hydrolases (BSH) with reduced fecal conjugated bile acids suggesting that dietary fiber regulates BSH activity via GHs. Mechanistic evidence supporting this notion was generated via fecal and plasma bile acid profiling in a healthy human fiber-free dietary intervention study as well as in a dietary fiber mouse experiment. Gaussian mixture modeling of fecal bile acids was used to identify three clinically relevant SBS phenotypes. Dietary fiber is associated with bile acid deconjugation likely via an interaction between gut microbiota BSHs and GHs in the small intestine, which may lead to whole food intolerance in patients with SBS. This mechanism not only has potential utility in clinical phenotyping and targeted therapeutics in SBS based on bile acid metabolism but may have relevance to other intestinal disease states.

The Effects of the Affordable Care Act on Utilization of Bariatric Surgery.

INTRODUCTION: The Affordable Care Act (ACA) expanded Medicaid (ME) and instituted Essential Health Benefits (EHB) that included bariatric surgery coverage on a state-by-state opt-in basis, increasing insurance coverage of bariatric surgery. MATERIALS AND METHODS: Using a difference-in-differences framework, changes in bariatric surgery rates, defined as utilization in the population of people with obesity, before and after the ACA were evaluated in four states. Bariatric surgery procedure data were taken from the Healthcare Cost and Utilization Project's State In-patient Database 2012-2015. Adjusted multivariable regressions were run in the Medicaid and commercially insured populations. RESULTS: We identified 36,456 bariatric surgeries across the 286 Health Service Areas and time periods, with 31,732 covered by commercial insurers and 4724 covered by Medicaid. An unadjusted increase in utilization rates was seen in the Medicaid and Commercial populations in both ME- and EHB-covered states as well as non-expansion and EHB opt-out states over time. In the Medicaid population, after adjusting for confounders, there was a significant increase of 24.77 cases per 100,000 people with obesity (95% confidence interval: 12.41, 37.13) in the expansion states relative to the control and pre-period. The commercial population experienced a nonsignificant change in the rates of bariatric surgery, decreasing by 2.89 cases per 100,000 people with obesity (95% confidence interval: - 21.59, 15.81). CONCLUSIONS: There was a significant increase in bariatric surgery rates among Medicaid beneficiaries associated with Medicaid expansion, but there was no change among the commercially insured.

Laparoscopic Sleeve Gastrectomy Carries a Lower Perioperative Mortality Including Sudden Cardiac Death over Roux-en-Y Gastric Bypass in Patients with a Prior Cardiac History: An MBSAQIP Analysis.

BACKGROUND: Although bariatric surgery has proven beneficial for those with cardiovascular disease (CVD), the overall and procedure-specific risk associated with bariatric surgery in this patient population remains unknown. DESIGN: Patients who underwent primary laparoscopic, laparoscopic-assisted, or robotic-assisted Roux-En-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at a MBSAQIP-accredited center were included (n = 494,611). Exposures include history of MI, PCI, or cardiac surgery who underwent RYGB or SG. Outcome measures were 30-day mortality, perioperative cardiac arrest, and rehospitalization. RESULTS: Of 494,611 patients enrolled in MBSAQIP, 15,923 had a history of MI, PCI, or cardiac surgery (prior cardiac history). Patient history of MI, PCI, and cardiac surgery was associated with significantly increased adjusted risk of perioperative cardiac arrest requiring CPR (OR: 2.31, 2.12, 2.42, respectively) and adjusted 30-day mortality (OR: 1.72, 1.50, 1.68, respectively). Prior cardiac history was associated with increased adjusted 30-day readmission rate (MI - OR, 1.42; PCI - OR, 1.45; and cardiac surgery - OR, 1.68). Further, 30-day postoperative readmission, postoperative cardiac arrest, and death were lower for patients undergoing SG compared to RYGB (OR: 0.48, 0.49, and 0.54 respectively). CONCLUSION AND RELEVANCE: Prior cardiac history was associated with significant greater risk of perioperative cardiac arrest and 30-day mortality among patients undergoing bariatric surgery. SG was associated with less adverse events than RYGB among this population. While there is a clear benefit to weight loss in patients with CVD, it is important to consider whether cardiac patients considering bariatric surgery may require additional preoperative optimization, perioperative interventions, and postoperative monitoring.

Defining postoperative weight change after pancreatectomy: Factors associated with distinct and dynamic weight trajectories.

BACKGROUND: Weight change offers the simplest indication of a patient's recovery after an operation. There have been no studies that have thoroughly investigated postoperative weight dynamics after pancreatectomy. The aim of this study was to define postoperative weight change after a pancreatectomy and determine factors associated with optimal and poor weight trajectories. METHODS: From 2004 to 2019, 1,090 proximal (65%) and distal (35%) pancreatectomies were performed in patients with adequate data in the medical records. Patient weights were acquired preoperatively and at postoperative months 1, 3, and 12. Optimal (top quartile, weight restoration) and poor (bottom quartile, persistent weight loss) postoperative weight cohorts were identified at 1 year postoperatively. RESULTS: The median percentage weight change 1 year postpancreatectomy was -6.6% (interquartile range: -1.4% to -12.5%), -7.8% for proximal pancreatectomy, and -4.2% for distal pancreatectomy. For most patients (interquartile range cohort), the median percentage weight change at 1, 3, and 12 months was -6.2%, -7.2%, and -6.6%. The independent factors associated with weight restoration were age <65, nonobesity (body mass index <30kg/m2), receiving total parenteral nutrition/total enteral nutrition preoperatively, experiencing preoperative weight loss >10%, distal pancreatectomy, not undergoing vascular resection, and no readmission within 30 days. Conversely, persistent weight loss was associated with American Society of Anesthesiologists classes III to IV, obesity, malignancy, proximal pancreatectomy, blood loss ≥350mL, and experiencing readmission within 30 days. Focusing on pancreatic ductal adenocarcinoma (n = 372) patients, the factors associated with persistent weight loss were obesity, proximal pancreatectomy, and experiencing recurrence within 1 year; however, weight cohorts were not associated with overall survival for pancreatic ductal adenocarcinoma patients. CONCLUSION: These data define weight kinetics after pancreatectomy. Ultimately, postoperative weight trajectories appear to be largely predetermined but may be mitigated by limiting readmissions and complications. Clinicians should use these data to identify patients who continue to lose weight between the first and third month postoperatively with a high suspicion for the requirement of nutritional monitoring or other interventions.

Challenges in obesity and primary aldosteronism: Diagnosis and treatment.

BACKGROUND: Obese patients may have unrecognized primary aldosteronism due to high rates of concomitant hypertension. We hypothesized that obesity impacts the diagnosis and management of patients with primary aldosteronism. METHODS: We conducted a retrospective analysis of all primary aldosteronism patients (n = 418) who underwent adrenal vein sampling (1997-2017). Patients were classified by body mass index as obese (body mass index ≥35) or nonobese (body mass index <35) and diagnostic evaluation was compared between groups. Within the operative cohort (n = 285), primary outcomes were changes in both blood pressure and antihypertensive medications after adrenalectomy. Secondary outcome was clinical resolution by Primary Aldosteronism Surgery Outcomes criteria. RESULTS: Thirty-five percent of patients were obese. Obese patients were more likely to be male (67.8% vs 56.1%, P = .025), somewhat younger (51.5 vs 54.4 years old, P < .012), and require more preoperative antihypertensive medications (6.7 vs 5.7, P = .04) than nonobese patients. Obese patients had lesser rates of radiologic evidence of adrenal tumors (68.4 vs 77.9%, P = .038) despite similar rates of lateralization on adrenal vein sampling. In the operative subset, obese patients had somewhat smaller tumors on final pathology (1.1 vs 1.5 cm, P = .014) but similar rates of complete and partial clinical resolution (P = 1.000). CONCLUSION: Obese primary aldosteronism patients have lesser rates of localization by imaging, likely due to smaller tumor size, however, experience similar benefit from adrenalectomy.

Reply to "Utility of Unrefined Carbohydrates in Type 2 Diabetes. Comment on Reversing Type 2 Diabetes: A Narrative Review of the Evidence, Nutrients, 2019, 11, 766".

We appreciate the interest and comments from Joshi et al [...].

Reversing Type 2 Diabetes: A Narrative Review of the Evidence.

BACKGROUND: Type 2 diabetes (T2D) has long been identified as an incurable chronic disease based on traditional means of treatment. Research now exists that suggests reversal is possible through other means that have only recently been embraced in the guidelines. This narrative review examines the evidence for T2D reversal using each of the three methods, including advantages and limitations for each. METHODS: A literature search was performed, and a total of 99 original articles containing information pertaining to diabetes reversal or remission were included. RESULTS: Evidence exists that T2D reversal is achievable using bariatric surgery, low-calorie diets (LCD), or carbohydrate restriction (LC). Bariatric surgery has been recommended for the treatment of T2D since 2016 by an international diabetes consensus group. Both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) now recommend a LC eating pattern and support the short-term use of LCD for weight loss. However, only T2D treatment, not reversal, is discussed in their guidelines. CONCLUSION: Given the state of evidence for T2D reversal, healthcare providers need to be educated on reversal options so they can actively engage in counseling patients who may desire this approach to their disease.

Ketogenic Diet: an Endocrinologist Perspective.

PURPOSE OF REVIEW: Obesity and its related comorbidities make up a large part of healthcare expenditures. Despite a wide array of options for treatment of obesity, rates of sustained weight loss continue to be low, leading patients to seek alternative treatment options. Although the first medically utilized ketogenic diet was described nearly 100 years ago, it has made a resurgence as a treatment option for obesity. Despite increased popularity in the lay public and increased use of ketogenic dietary strategies for metabolic therapy, we are still beginning to unravel the metabolic impact of long-term dietary ketosis. RECENT FINDINGS: There are a number of recent trials that have highlighted the short- and long-term benefits of ketogenic diet on weight, glycemic control, and other endocrine functions including reproductive hormones. This review is a summary of available data on the effectiveness and durability of the ketogenic diet when compared to conventional interventions. Ketogenic dietary strategies may play a role in short-term improvement of important metabolic parameters with potential for long-term benefit. However, response may vary due to inter-individual ability to maintain long-term carbohydrate restriction.

Saturated Fat: Part of a Healthy Diet.

PURPOSE OF REVIEW: Despite the American public following recommendations to decrease absolute dietary fat intake and specifically decrease saturated fat intake, we have seen a dramatic rise over the past 40 years in the rates of non-communicable diseases associated with obesity and overweight, namely cardiovascular disease. The development of the diet-heart hypothesis in the mid twentieth century led to faulty but long-held beliefs that dietary intake of saturated fat led to heart disease. Saturated fat can lead to increased LDL cholesterol levels, and elevated plasma cholesterol levels have been shown to be a risk factor for cardiovascular disease; however, the correlative nature of their association does not assign causation. RECENT FINDINGS: Advances in understanding the role of various lipoprotein particles and their atherogenic risk have been helpful for understanding how different dietary components may impact CVD risk. Numerous meta-analyses and systematic reviews of both the historical and current literature reveals that the diet-heart hypothesis was not, and still is not, supported by the evidence. There appears to be no consistent benefit to all-cause or CVD mortality from the reduction of dietary saturated fat. Further, saturated fat has been shown in some cases to have an inverse relationship with obesity-related type 2 diabetes. Rather than focus on a single nutrient, the overall diet quality and elimination of processed foods, including simple carbohydrates, would likely do more to improve CVD and overall health. It is in the best interest of the American public to clarify dietary guidelines to recognize that dietary saturated fat is not the villain we once thought it was.

Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome.

PURPOSE OF REVIEW: The goal of this paper is to review current literature on nutritional ketosis within the context of weight management and metabolic syndrome, namely, insulin resistance, lipid profile, cardiovascular disease risk, and development of non-alcoholic fatty liver disease. We provide background on the mechanism of ketogenesis and describe nutritional ketosis. RECENT FINDINGS: Nutritional ketosis has been found to improve metabolic and inflammatory markers, including lipids, HbA1c, high-sensitivity CRP, fasting insulin and glucose levels, and aid in weight management. We discuss these findings and elaborate on potential mechanisms of ketones for promoting weight loss, decreasing hunger, and increasing satiety. Humans have evolved with the capacity for metabolic flexibility and the ability to use ketones for fuel. During states of low dietary carbohydrate intake, insulin levels remain low and ketogenesis takes place. These conditions promote breakdown of excess fat stores, sparing of lean muscle, and improvement in insulin sensitivity.

Obesity and Breast Cancer: A Complex Relationship.

As prevalence of obesity continues to rise in the United States, we are beginning to elucidate the complex role of obesity-associated chronic inflammation, endocrine dysfunction, and hormone production as a driver for increased breast cancer risk. Epidemiological data suggest that obesity (BMI > 30) is associated with increased breast cancer incidence, worse prognosis, and higher mortality rates. Mechanistically, obesity and excess fat mass represent a state of chronic inflammation, insulin resistance, adipokine imbalance, and increased estrogen signaling. This pro-tumorigenic environment stimulates cancer development through abnormal growth, proliferation, and survival of mammary tissue. Importantly, obesity is a modifiable risk factor; alterations in cell proliferation, apoptosis, circulating estrogen, and insulin sensitivity are observed in response to weight loss attainable through behavior modification including dietary and exercise changes.

Adrenal myelolipoma: operative indications and outcomes.

BACKGROUND: Adrenal myelolipoma (AM) is a benign lesion for which adrenalectomy is infrequently indicated. We investigated operative indications and outcomes for AM in a large single-institution series. SUBJECTS AND METHODS: A retrospective cohort study of prospectively collected data was conducted. Patients (≥16 years of age) who underwent adrenalectomy in the Division of General Surgery at Barnes-Jewish Hospital (1993-2010) were grouped by operative indication (myelolipoma versus other pathology) and compared using nonparametric tests (α<0.05). RESULTS: Sixteen patients (4.0%) had myelolipomas resected out of 402 patients who underwent adrenalectomy. Fourteen patients with suspected AM underwent adrenalectomy, 13 (93%) of whom had AM confirmed on pathology. Indications for adrenalectomy were abdominal or flank pain, large tumor size (>8 cm), atypical radiologic appearance, and/or inferior vena cava compression. Three patients with suspected other adrenal lesions had AM confirmed on final pathology. Operative approach was laparoscopic in 15 cases and open in 1 case of a 21-cm lesion. Patients who underwent laparoscopic adrenalectomy for AM (n=15) or other adrenal pathology (n=343) were similar with respect to age, gender, American Society of Anesthesiologists classification, prior abdominal operation, tumor side, operative time, conversion rate, estimated blood loss, intraoperative complications, hospital length of stay, and 30-day morbidity. However, patients with resected AM had a higher body mass index (36.5±8.1 kg/m(2) versus 30.1±7.5 kg/m(2); P<.01) and a larger preoperative tumor size (8.4±3.0 cm versus 3.1±1.7 cm; P<.01). CONCLUSIONS: Laparoscopic adrenalectomy may be appropriate for patients with a presumptive diagnosis of AM and abdominal or flank pain, large tumor size, and/or uncertain diagnosis after imaging. Outcomes and morbidity following LA for AM and other adrenal pathology appear comparable.